Dr. Herbert Meltzer
Vanderbilt research leads to FDA approval of first suicide-reducing drug
The antipsychotic drug Clozaril has received the Food and Drug Administration’s first indication for reducing the risk of recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder. The decision, announced Dec. 19, was due in large part to an international clinical trial led by Vanderbilt’s Dr. Herbert Y. Meltzer, director of the Division of Psychopharmacology, that compared Clozaril to the more commonly prescribed drug Zyprexa.
About 1 percent of the general population worldwide has schizophrenia or the closely related schizoaffective disorder; more than 2 million Americans suffer from the diseases. Over their lifetime, as many as 40 percent of people with these disorders will attempt suicide and 10 percent of them will die due to suicide. Annually in the United States, there are an estimated 40,000 serious suicide attempts among people with schizophrenia and 80,000 hospitalizations to prevent attempts. The lives of about 4,000 people with schizophrenia or schizoaffective disorder end by suicide.
The January edition of Archives of General Psychiatry chronicles results of the International Suicide Prevention Trial (InterSePT), which show Clozaril, made by Novartis, reduced suicide and hospitalization for suicidal behavior among people with schizophrenia or schizoaffective disorder by 26 percent compared to Zyprexa, which could translate into an estimated 1,000 U.S. lives saved each year.
“There would be 10,000 fewer suicide attempts and 20,000 fewer hospitalizations annually, with greatly reduced costs for treatment and, of course, suffering to the individuals and their families,” said Meltzer, the Bixler/Johnson/Mays Professor of Psychiatry.
“Suicide is the most feared outcome in the field of mental health treatment,” Meltzer said. “The remarkable finding from InterSePT is that treatment with clozapine reduced suicidal events by up to a quarter over and above an established and effective antipsychotic.”
InterSePT began in 1998 and randomized 980 subjects at 67 sites in 11 countries, including 13 patients at Vanderbilt, received, on average, 275 mg. per day of Clozaril or 17 mg. per day of olanzapine (Zyprexa) for the duration of the two-year study. Most people on Clozaril chose to continue it after the study ended. The drug reduced the number of suicidal behaviors (actions by a patient that put that patient at risk of death) compared to Zyprexa by 25 percent.
The study also found that the amount of frequency of additional medications required to improve mood and suicidality was significantly less with Clozaril.
Meltzer initiated the interest in the possibility that Clozaril had special effectiveness to reduce suicide in 1994 when he and a psychiatric research assistant, Dr. Ghadeer Okayli, found an 80 percent reduction in the number of people who made at least one suicide attempt among 88 people with schizophrenia who took the drug compared to the frequency in the two years before beginning treatment with Clozaril. Yet a fear of agranulocytosis, a potentially fatal complication that drastically decreases white blood cell counts, which Meltzer believes is disproportionate to the true risk, has prevented the drug from being widely used for patients who have persistent delusions and hallucinations, despite adequate trials with other antipsychotic drugs. The drug is now prescribed as a last resort, to about 5 percent of people with schizophrenia who have not benefited from Zyprexa, Risperdal, Geodone or Seroquel, the mainstays of current treatment for schizophrenia and schizoaffective disorder, which are prescribed, Meltzer estimates, to about 85 percent of the patients, the rest receiving the first generation of antipsychotics such as Haldol.
Subsequent studies, including a key Boston University epidemiology study in 1995 of all 65,000 people who had been started on Clozaril, provided strong evidence for a marked decrease in suicide deaths for those who continued to take the drug.
Meltzer proposed that Novartis fund a clinical trial to compare Clozaril to Zyprexa in order to establish its ability to reduce the risk of suicide. But the drug’s patent was running out, opening the door for generics while closing a window of opportunity, in the form of economic incentives for the drug maker, to study the drug in a controlled clinical trial.
Officials in the FDA’s psychopharmacology division first balked, then changed their minds after they reconsidered the issue of “pseudospecificity.” Until then, all new drugs for schizophrenia had to prove they were effective in treating delusions and hallucinations but not the totality of the symptoms and signs, which include cognitive impairment, negative symptoms (withdrawal, lack of motivation, anhedonia and diminished energy), mood and anxiety symptoms. Pseudospecificity eliminated the possibility that these other elements of the disease could be separate targets for treatment with drugs.
“This idea represented an overvaluation of the gains to be achieved by treating psychosis,” Meltzer said. “It was very apparent that was not the correct view. The various types of symptoms can be readily shown to be independent elements; beneath that they may stem from independent biology, including genetic factors.”
Presented with the results of the Clozaril study, the FDA acknowledged that the pseudospecificity perspective no longer governs their approach to approval of drugs for schizophrenia.
“I believe this will have a great impact on stimulating more research to tackle other components of the illness, especially cognitive function, which I personally believe is the key feature of the illness that causes it to have such a devastating effect on work and social function,” Meltzer said.
In 1994 Meltzer and colleagues published the first evidence that any antipsychotic drug (they studied Clozaril) could significantly improve the cognitive impairment in schizophrenia. “Understanding this effect, which is shared to a greater or lesser extent by all the new antipsychotic drugs, is the major focus of our clinical and preclinical research,” Meltzer said. His group includes Drs. Junji Ichikawa, Myung Lee and Tianlai Tang.
The FDA’s blessing gives Novartis the exclusive right to market Clozaril for people with schizophrenia at risk of suicide, which led to the company’s funding of InterSePT.
“It shows how good clinical, bedside observations can identify possible treatments, that can then lead to research collaborations between academia and industry,” Meltzer said.
The study could lead to clinical trials of Clozaril to prevent suicide in people with bipolar disorder, a disease that affects as many people as schizophrenia but carries twice the rate of suicide deaths. It has also focused the attention of the American Psychiatric Association, which will soon publish new guidelines for treating suicidal patients in all diagnoses.